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Atrial Fibrillation:Risk factor or risk marker? What are the differences?
Jeff Healey MD, MSc, FRCPC
Population Health Research Institute
McMaster University
Hamilton, Canada
Disclosures
• Research Grants
• Medtronic, Boston Scientific, St. Jude Medical, Boehringer-Ingelheim, Bayer,
Bristol-Meyers-Squibb
• Speaking Fees
• Medtronic, Boston Scientific, St. Jude Medical, Boehringer-Ingelheim, Bayer,
Bristol-Meyers-Squibb
Speaker
What is Causality?
• Aristotle
• Formal, Material, Efficient and Final causes
• Hume
• Can never be sure;
• Cause and effect must be contiguous in space and time; cause must occur before
the effect and there be a constant union between the two
• Similar constructs in Hindu and Buddhist philosophy
• Multiple causal models and theories to help “prove” causation
Speaker
Criteria for Causation: Sir Austin Bradford Hill
Factor AF and Stroke
Strength 2-6-fold increased RR, OR, HR; PAR high, but confounding
Consistency Observation in many populations, CHADS-VASc
Specificity Difficult –many types and “causes” of stroke
Temporality Difficulty defining all AF; post-stroke monitoring studies
Biological gradient Unclear AF threshold for clinical AND sub-clinical AF
Plausibility Pathology and TE echo studies; but small and/or old; cannot see all thrombi
Coherence Animal models; but easy to adapt; relevance to SCAF?
Experimental Data lacking, RCTs in AF – both drug and device
Analogy Many but not specific
Speaker
“Serial sections of the left atrial appendage were prepared
[in AF-patients with embolic stroke]…in every case mural
thrombus, not obvious to the naked eye, was found in the
interstices of the trabeculae carneae.”
C.M. Fisher. Can Med Assoc J 1953; 69: 257.
1913-2012 (b. Waterloo, Ontario)
0
10
20
30
Wolf et al. Stroke 1991;22:983-988.
50–59 60–69 70–79 80–89
%
AF prevalence
Strokes attributable to AF
Age Range (years)
Strokes Attributable to AF
Framingham Study
ASSERT: Clinical OutcomesHealey JS, NEJM 2012
Event
Device-Detected Atrial Tachyarrhythmia Device-Detected Atrial
Tachyarrhythmia Present vs. absentAbsent
N=2319PresentN= 261
events %/year events %/ year RR 95% CI p
Ischemic Stroke or Systemic Embolism
40 0.69 11 1.69 2.49 1.28 – 4.85 0.007
Vascular Death 153 2.62 19 2.92 1.11 0.69 – 1.79 0.67
Stroke / MI / VascularDeath
206 3.53 29 4.45 1.25 0.85 – 1.84 0.27
Clinical Atrial Fibrillation or Flutter
71 1.22 41 6.29 5.56 3.78 – 8.17 <0.001
ASSERT: Time-Dependent Analysis
Duration of AT ≥ 190 Beats per
Minute
Ischemic Stroke or Embolism:
Atrial Tachyarrhythmia Present
vs. Absent
RR 95% CI P-Value
≥ 6 minutes 1.77 1.01-3.10 0.047
≥ 30 minutes 2.01 1.12-3.60 0.02
≥ 6 hours 2.99 1.55-5.77 0.001
≥ 24 hours 4.96 2.39-10.3 <0.001
ASSERT: Outcomes by CHADS2Healey JS, NEJM 2012
CHADS2
ScoreTotal Pts.
Sub-clinical Atrial Tachyarrhythmia between enrollment and 3 months Sub-clinical Atrial
Tachyarrhythmia
Present vs. absentPresent Absent
Pts. events%/yea
rPts.
events
%/year HR 95% CIP
(trend)
1 600 68 1 0.56 532 4 0.28 2.110.23 –18.9
0.352 1129 119 4 1.29 1010 22 0.77 1.830.62 –5.40
>2 848 72 6 3.78 776 18 0.97 3.931.55 –9.95
Risk Factor Score
Congestive Heart
Failure
1
Hypertension 1
Age ≥ 75 1
Diabetes Mellitus 1
Stroke/TIA/
Thromboembolism
2
Maximum Score 6
0
4
8
12
16
20
0 1 2 3 4 5 6
Stroke rate/ 100 patient yr
CHADS2
1.9%
Stroke Risk by Clinical Factors
Outcomes of Cohort StudyBinici, Circulation 2010
Death or Stroke Hospitalization for AF
P=0.0366 P=0.014
Copenhagen Holter Study: Age 55-75. One 48 hour Holter.Positive defined as > 30 PACs per hour or any run ≥ 20 beats. Mean follow-up of 6.3 years
Challenges to Proof of Causality
• Defining AF
• Monitoring studies
• AF vs. SCAF vs. atrial tachycardia vs. PACs
• Historical studies mostly persistent/permanent AF
• Defining Surrogates
• LAA clot vs. spontaneous echo contrast (smoke)
• Defining Outcomes
• Stroke
• Covert stroke
• Cognitive decline
• Determining Temporal Relationship
• Experiment…
Speaker
Centres N Follow-
up (mo)
CHADS2 score OAC stopped Events per year in OAC
stopped
Oral 200644 Single US 522 25 Not stated 78% of CHADS
0 and 68% ≥1
0
Nademanee 200845 Single US 517 26 Not stated; mean about 1 84% 0.4% per year
Themistoclakis
201046
5 US/ Europe 3555 28 60%=0, 27%=1, 13% =2 80.2% 0.04% strokes per year
Chao 201147 Single Taiwan 565 39 Median 1 Not clear 1.5% stroke/TIA per year for
whole group (i.e on and off
OAC)
Saad 201148 Single Brazil 327 46 Mean 1.89 91% 0
Yagishita 201149 Single Japan 524 44 0-1=85%, 2 or more=15% 82% 0.16% per year
Hunter 201250 7 UK/
Australia
1273 36 (in those stopping OAC) 57%
=0, 34% =1, 7% >1
64% 0.16% stroke/TIA Per year
Guiot 201251 Single US 1016 34 Mean 1.1 60% 1% stroke per year
Reynolds 201252 US
multicenter
812 36 40% 3.4 % stroke/TIA per year for
whole group (i.e. on and off
OAC)
Bunch 201353 Single US 4212 36 20%=0, 20%=1, 5%=2, 56%>2 Not included 1.5% risk of stroke per year in
ablation arm
Gaita 201454 Single Italy 766 60.5 84%=0 or 1, 16%= 2+, 5%=3+ 64% (all pts
with CHADS or
more)
0.2 per 100 patient years for
those off OAC
Stroke risk after AF ablation
Does atrial fibrillation cause stroke?
• Difficult to say with certainty in all cases where the two conditions are sequentially associated
• In some cases, the conventional paradigm is undoubtedly true
• In others, it is undoubtedly false
• Some strategies to prevent AF-associated stroke depend on our understanding of causality, while others do not
Speaker
LAAOS-III
• Most strokes (70%) in AF patients are cardio-embolic originating from the LAA
• 90% of the clots are in the LAA in AF patients
• N=3500; both receiving and not receiving OAC
=